Kemp et al. Alzheimer's Research & Therapy (2017) 9:19 DOI 10.1186/s13195-017-0242-1
RESEARCH
Open Access
Cognitive profile in prodromal dementia with Lewy bodies Jennifer Kemp1,2,3,4*, Nathalie Philippi1,2,3,4, Clélie Phillipps1,2,3, Catherine Demuynck1,2,3, Timothée Albasser1,2,3, Catherine Martin-Hunyadi1,2,3, Catherine Schmidt-Mutter5, Benjamin Cretin1,2,3,4 and Frédéric Blanc1,2,3,4,5
Abstract Background: Cortical and subcortical cognitive impairments have been found in dementia with Lewy bodies (DLB). Roughly, they comprise visuoconstructive and executive dysfunction, whereas memory would remain relatively spared. However, the cognitive profile of patients with prodromal DLB remains poorly illustrated to date. Methods: We included 37 patients with prodromal DLB (age 67.2 ± 8.6 years, 18 men, Mini Mental State Examination [MMSE] score 27.4 ± 2) and 29 healthy control subjects (HCs; age 68.8 ± 7.9 years, 15 men, MMSE score 29.0 ± 0.9). They were presented with an extensive neuropsychological test battery to assess memory; speed of processing; executive function; visuoperceptual, visuospatial and visuoconstructive abilities; language; and social cognition. Results: Compared with HCs, patients had lower scores on a visual recognition memory test (Delayed Matching to Sample-48 items; p ≤ 0.021) and lower free recall (all p ≤ 0.035), but not total recall, performance on a verbal episodic memory test (Free and Cued Selective Reminding Test). Short-term memory (p = 0.042) and working memory (p = 0.002) scores were also lower in patients. Assessment of executive function showed no slowing but overall lower performance in patients than in HCs (all p ≤ 0.049), whereas assessment of instrumental function yielded mixed results. Indeed, patients had lower scores on language tests (p ≤ 0.022), apraxia for pantomime of tool use (p = 0.002) and imitation of meaningless gesture (p = 0.005), as well as weakened visuospatial abilities (p = 0.047). Visuoconstruction was also impaired in patients. However, visuoperceptual abilities did not differ between groups. Finally, theory of mind abilities were lower in patients than in HCs (p < 0.05), but their emotion recognition abilities were similar. Conclusions: This study presents the cognitive profile in patients with prodromal DLB. In line with the literature on DLB with dementia, our results show lower performance on tests of executive function and visuoconstruction. However, we found, from a prodromal stage of DLB, memory (free recall and visual recognition) and social cognition deficits, as well as weakened visuospatial and praxic abilities. Keywords: Dementia with Lewy bodies, Cognition, Cognitive profile, Prodromal, Mild cognitive impairment
Background Dementia with Lewy bodies (DLB) is the second most common form of degenerative dementia after Alzheimer’s disease (AD), with prevalence rates of up to 5% in the elderly population and up to 30% of all dementia cases [1, 2]. A recent review showed that, on the basis of 2005 revised International Consensus Criteria for DLB [1], DLB * Correspondence: [email protected] 1 Neuropsychology Unit, Neurology Department, University Hospitals of Strasbourg, Strasbourg, France 2 Geriatrics Department, University Hospitals of Strasbourg, Geriatric Day Hospital, Strasbourg, France Full list of author information is available at the end of the article
represents about 4% of dementia cases diagnosed in the community and 7.7% in secondary care [3]. DLB involves a progressive reduction in cognitive functioning, characterised by fluctuations in cognition and alertness, visual hallucinations and parkinsonism. The presence of two or three of these core signs is sufficient for a diagnosis of probable DLB [1]. Patients with DLB are also likely to present with rapid eye movement sleep behaviour disorder (RBD) and severe neuroleptic sensitivity. Other features, which are less specific, are repeated falls, autonomic dysfunction and depression.
© The Author(s). 2017 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
Kemp et al. Alzheimer's Research & Therapy (2017) 9:19
Research on prodromal DLB—that is, the disease is present but cognitive impairment is not sufficient to lead to functional deficits in activities of daily living [4]—is relatively recent. Several features have been described in prodromal DLB [5]. For instance, behavioural and psychiatric symptoms, such as visual hallucinations, RBD, depression, anxiety and delirium, can be present very early and prior to the onset of memory impairment in DLB [6–8]. Similarly, physical symptoms, including constipation, hyposmia and postural dizziness, have been described to appear years before memory loss in prodromal DLB [7]. Pathological studies of Lewy body disease suggest that the olfactory bulb and the peripheral autonomic nervous system, including the enteric nervous system, constitute the first sites of involvement (e.g., [9, 10]). Moreover, we recently demonstrated in a neuroimaging study that patients with prodromal DLB have thinner grey matter in the right insula, superior temporal and orbitofrontal cortices than healthy control subjects (HCs) and patients with prodromal AD [11]. Similarly, we showed that patients with prodromal DLB present with diminished grey matter volumes of bilateral insulae and right anterior cingulate cortex compared with HCs [12]. Functional imaging studies using [18F]fluoro-D-glucose positron emission tomography furthermore showed that patients with prodromal DLB symptoms have occipital hypometabolism [13]. Only a few studies have examined the cognitive profile of prodromal DLB, whereas cognitive impairment has been relatively well documented in patients with moderate DLB, especially compared with patients with AD or patients with Parkinson’s disease (PD) (for reviews, see [14–16]). For instance, moderate DLB is generally associated with prominent deficits on executive function tests (e.g., [17–19]), whereas verbal episodic memory and naming abilities remain rather spared (e.g., [20]). Moreover, numerous studies have shown visuoperceptual and visuospatial impairment (e.g., [14, 21]). Finally, attention is also affected, with reduced sustained and divided attention abilities and increased attentional fluctuations (e.g., [22–24]). Studies on cognition in prodromal DLB also have been focused on the comparison with prodromal AD or PD and have revealed that patients with prodromal DLB have more visuospatial and letter fluency deficits and less memory storage deficits [25–27]. These findings are in line with the suggestion that impairment in nonmemory domains (e.g., executive function, visuospatial abilities) is more likely to progress to DLB than single-domain amnestic mild cognitive impairment (MCI) [25, 27]. Researchers in a recent study assessed cognition in mild and very mild DLB [28]. The authors found that very mild DLB was associated with impairment of attentional/executive, visuospatial, visuoconstructive and naming abilities, as well
Page 2 of 10
as with difficulties in retrieval of episodic memory. With the progression to mild DLB, the authors found that executive function impairment increased, resulting in reduced performance on tests of inhibition, mental flexibility and verbal initiation. The aim of the present study was to draw a cognitive profile of patients with prodromal DLB by means of an extensive neuropsychological evaluation comprising memory, executive function, instrumental function and social cognition tests. Therefore, we compared the performance on cognitive tests of patients with prodromal DLB with normative data as well as with the performance of elderly HCs.
Methods Participants, diagnosis and assessments
Thirty-seven patients with prodromal DLB and 29 HCs were enrolled in the present study. Patients were recruited from the tertiary memory clinic of Strasbourg University Hospitals, Strasbourg, France, including the neurology and geriatrics departments. HCs were recruited from among friends and relatives of the patients or from among participants attending the hospital’s clinical investigation centre. Patients with prodromal DLB were defined as patients with MCI (Petersen’s criteria [29] and McKeith’s criteria [1]) or with probable DLB criteria (i.e., two core symptoms), and this maps onto recent suggestions for potential prodromal DLB criteria [5, 30]. Preservation of independence in functional abilities was assessed in patients and HCs on the basis of four items [31] of the instrumental activities of daily living [32, 33] and the activities of daily living [34] questionnaires. Participants with two or more functional domains impaired, suggesting reduced autonomy, were not included in the present study. Exclusion criteria for all participants included history of alcohol/substance abuse, evidence suggesting alternative neurological or psychiatric explanations for symptoms/cognitive impairment (for patients) or the presence of other severe or unstable medical illness. Patients additionally underwent cerebrospinal fluid (CSF) analysis, including measurement of tau, phosphorylated tau (p-Tau) and amyloid-β (Aβ) 1–42 (INNOTEST β-amyloid(1–42) enzyme-linked immunosorbent assay; Fujirebio, Gent, Belgium). Assessment of medial temporal atrophy by brain magnetic resonance imaging (MRI) was performed in patients and HCs using the standardised Scheltens scale (five categories, 0–4 scale), with 0 corresponding to no atrophy [35]. Patients with concomitant DLB and AD (i.e., meeting both McKeith’s [1] and Dubois’s [36] criteria) were also excluded. More precisely, patients with DLB and two of the following features were excluded: episodic memory (storage) impairment, hippocampal atrophy (Scheltens scale of at minimum 2/4) and CSF abnormalities (at
Kemp et al. Alzheimer's Research & Therapy (2017) 9:19
minimum two abnormal CSF markers among p-Tau, Tau, Aβ42 [37]). Concretely, when hippocampal atrophy or CSF abnormalities were observed in a patient with DLB, performance on the Rappel libre/Rappel indicé à 16 items (RL/ RI-16,) was checked; a patient whose performance indicated storage impairment, testifying to the presence of two of the above-mentioned features, was excluded from analysis. However, a patient presenting solely with hippocampal atrophy, CSF abnormalities or storage impairment was not excluded if the criteria for DLB were met [1]. To assess specific cognitive domains, we used the neuropsychological tests outlined below. Assessment of memory
For the assessment of memory, we used the following tests: The French version of the Free and Cued Selective
Reminding Test (RL/RI-16 [38]): This verbal memory test is based on semantic cuing, which allows controlling for encoding and facilitates retrieval. Sixteen words are presented that are associated with a category cue. Participants are asked to recall the words in three successive trials, then to recognise the 16 items between 32 distractors before recalling them in a 30-minute delayed trial. Each trial includes free recall (FR) and cued recall (CR) tasks whereby the category cue is provided for the items not spontaneously recalled. The total recall (TR) score is the sum of the FR and the CR. The Delayed Matching to Sample-48 items (DMS-48 [39]): The DMS-48 consists of a visual forced-choice recognition test. After an implicit encoding phase where 48 coloured items are presented, an immediate recognition trial (set 1) and a 1-h delayed recognition trial (set 2) are proposed in which participants are asked to choose between the target and a distractor. Two different sets of distractors are used. Forward and backward digit spans [40]: These tests allow evaluation of short-term and working memory. The short-term memory span is the longest list of numbers the participant can recall in correct order immediately after presentation. Backward memory span is the longest list of numbers the participant can recall in reverse order immediately after presentation. Assessment of executive function
For the assessment of executive function, we used the following tests: Frontal Assessment Battery (FAB [41]): The FAB
briefly assesses six cognitive function domains
Page 3 of 10
sustained by the frontal lobes: conceptualisation, mental flexibility, motor programming, sensitivity to interference, inhibitory control and environmental autonomy. Three points are awarded for every perfect response (maximum score 18). Trail Making Test (TMT) A and B [42]: Both parts consist of 25 circles distributed over a sheet of paper. In TMT A, the circles are numbered 1–25, and the participant is asked to draw lines to connect the numbers in ascending order as quickly as possible. In the TMT B, the circles include both numbers (1–13) and letters (A–L). The participant has to draw lines to connect the circles in an ascending pattern as quickly as possible while alternating between the numbers and letters. The completion time and the number of errors are recorded. Formal lexical evocation [43]: The participant is asked to generate as many words as possible that start with the letter P within 2 minutes. Assessment of processing speed
For the assessment of processing speed, we used the digit symbol substitution test [40]. This test involves a key in which the numbers 1–9 are each paired with a unique symbol. Below the key, the numbers 1–9 are shown in random order. The participant is allowed 120 seconds to fill in the corresponding symbol for each number. Assessment of instrumental function
For the assessment of instrumental function, we used the following tests: An oral naming test [44] of 80 pictures (maximum
score 80) and formal semantic evocation [43] were used to evaluate language. Formal semantic evocation consists of generating as many names of animals as possible within 2 minutes. Rey-Osterrieth Complex Figure test (ROCF [45]): Participants were presented with the ROCF stimulus card and asked to draw the same figure. The figure is subcategorised into 18 elements, and these are scored on the basis of their presence, completeness and correct placement (0.5, 1 or 2 points per element; maximum score 36). The following subtests using the Visual Object and Space Perception battery (VOSP [46]) allow the evaluation of visuoperceptual and visuospatial abilities: – Screening: The participant has to identify whether there is a degraded ‘X’ on 20 patterned sheets of paper. One point is given for each correct answer (maximum score 20).
Kemp et al. Alzheimer's Research & Therapy (2017) 9:19
– Incomplete letters: Twenty incomplete letters are shown, and the subject is asked to name or identify them. A point is awarded for each correct answer (maximum score 20). – Dot count: The participant is asked to count how many black dots there are on a white card. There are ten cards. A point is awarded for every correct count (maximum score 10). – Position discrimination: Ten boards are presented. Each board has two squares with a black dot in the centre each. In one of the squares, the point is exactly in the centre, whereas the other point is slightly off-centre. The participant is asked to identify the square in which the black spot is located exactly in the centre. The number of correct answers is recorded (maximum score 10). – ‘Number location’: Ten boards are presented in this test. Each board has two squares arranged one above the other. The top square contains numbers arranged randomly. The bottom square contains only a black dot. The participant is asked to identify which number corresponds to the black dot. Each correct identification earns 1 point (maximum score 10). – Cube analysis: Ten boards are presented. Each board features a design of solid structures. The participant is asked to identify how many solids (cubes) there are on each board. The boards are presented in increasing degree of difficulty (maximum score 10). Praxis is tested by the means of a brief battery [47] evaluating five symbolic gestures (scored 0 or 1 point), five pantomimes (scored 0, 1 or 2 points) and imitation of eight meaningless gestures (scored 0 or 1 point). Evaluation of social cognition
For the evaluation of social cognition, we used the following tests: Mini-Social Cognition & Emotional Assessment
(mini-SEA [48]) test battery: The mini-SEA comprises a facial emotion recognition test and a shortened version of the Faux Pas Recognition Test (FPRT [49]). Emotion recognition is assessed by means of 35 photographs from a series of pictures of facial affect [50]. The faces display one of the six basic emotions (i.e., happiness, sadness, disgust, fear, surprise and anger) or a neutral facial expression. After looking at each photograph, participants choose the emotion that best corresponds to their opinion of that facial expression. The maximum score, indicating best performance, is 35. The FPRT
Page 4 of 10
consists of ten short stories, five with and five without a faux pas. Each story has two types of questions, namely six theory of mind (ToM) questions and two control questions. The ToM questions assess the detection and understanding of faux pas and the understanding of the speaker’s and the listener’s mental states. One point is given for each correct answer on the faux pas questions, and two points are given for each correct rejection of control stories (maximum score 40). Raw scores are converted to weighted scores. Both scores are weighted out of 15, resulting in a total weighted score out of 30. French version of the Reading the Mind in the Eyes (RME) test [51]: This test evaluates the ability of an individual to determine the mental state of another individual by looking at a picture of the latter’s eyes. The task consists of 36 items showing the eye region of 36 different faces in black-and-white photographs. Each picture has four mental state terms printed below it, and the participant has to choose the word that best describes what the person in the photograph is feeling or thinking. The number of correct answers is recorded (maximum score 36). Data analyses
z-Scores were calculated using data derived from normal cohorts ([38–43, 46–48, 52] and Strauss and Spreen, unpublished). They are systematically adjusted for age, as well as for sex and education level when these data are available in the normal cohorts. z-Scores less than or equal to −1.65 are considered pathological. STATISTICA software (version 12.7; Statistica, Tulsa, OK, USA) was used for further statistical evaluation as required. Where appropriate, differences in demographic and clinical data were assessed using parametric (analysis of variance [ANOVA], t tests) and nonparametric (Kruskal-Wallis H, Mann-Whitney U) tests. For categorical measures, χ2 tests were applied. For neuropsychological tests, ANOVA for independent groups was used for the analysis of z-scores, and the nonparametric Kruskal-Wallis H test was used for the analysis of raw scores. For each test statistic, a probability value less than 0.05 was regarded as significant.
Results Participants’ characteristics
Demographic data for patients and HCs are summarised in Table 1. The groups did not differ in terms of age, education, sex and handedness. Cognition
Neuropsychological test results (raw scores and z-scores) of patients and HCs are reported in Table 2.
Kemp et al. Alzheimer's Research & Therapy (2017) 9:19
Page 5 of 10
Table 1 Demographic and clinical characteristics of patients and healthy control subjects Patients with DLB
n
37
29
Age, yearsa
67.19 (8.64)
68.79 (7.94)
NS
Education, years
11.97 (4.14)
13.18 (3.08)
NS
Sex, M/F
18/19
15/14
NS
Handedness, R/L
35/2
27/2
NS
IADL scorea,b
3.75 (0.50)
4 (0)
0.02
ADL scorea,c
5.89 (0.39)
6 (0)
NS
a
HCs
p Value
Characteristic
MCI single/multiple domains Amnestic
0/18
–
–
Non-amnestic
10/9
–
–
Rigidity
28/37 (76)
0/23
RESEARCH
Open Access
Cognitive profile in prodromal dementia with Lewy bodies Jennifer Kemp1,2,3,4*, Nathalie Philippi1,2,3,4, Clélie Phillipps1,2,3, Catherine Demuynck1,2,3, Timothée Albasser1,2,3, Catherine Martin-Hunyadi1,2,3, Catherine Schmidt-Mutter5, Benjamin Cretin1,2,3,4 and Frédéric Blanc1,2,3,4,5
Abstract Background: Cortical and subcortical cognitive impairments have been found in dementia with Lewy bodies (DLB). Roughly, they comprise visuoconstructive and executive dysfunction, whereas memory would remain relatively spared. However, the cognitive profile of patients with prodromal DLB remains poorly illustrated to date. Methods: We included 37 patients with prodromal DLB (age 67.2 ± 8.6 years, 18 men, Mini Mental State Examination [MMSE] score 27.4 ± 2) and 29 healthy control subjects (HCs; age 68.8 ± 7.9 years, 15 men, MMSE score 29.0 ± 0.9). They were presented with an extensive neuropsychological test battery to assess memory; speed of processing; executive function; visuoperceptual, visuospatial and visuoconstructive abilities; language; and social cognition. Results: Compared with HCs, patients had lower scores on a visual recognition memory test (Delayed Matching to Sample-48 items; p ≤ 0.021) and lower free recall (all p ≤ 0.035), but not total recall, performance on a verbal episodic memory test (Free and Cued Selective Reminding Test). Short-term memory (p = 0.042) and working memory (p = 0.002) scores were also lower in patients. Assessment of executive function showed no slowing but overall lower performance in patients than in HCs (all p ≤ 0.049), whereas assessment of instrumental function yielded mixed results. Indeed, patients had lower scores on language tests (p ≤ 0.022), apraxia for pantomime of tool use (p = 0.002) and imitation of meaningless gesture (p = 0.005), as well as weakened visuospatial abilities (p = 0.047). Visuoconstruction was also impaired in patients. However, visuoperceptual abilities did not differ between groups. Finally, theory of mind abilities were lower in patients than in HCs (p < 0.05), but their emotion recognition abilities were similar. Conclusions: This study presents the cognitive profile in patients with prodromal DLB. In line with the literature on DLB with dementia, our results show lower performance on tests of executive function and visuoconstruction. However, we found, from a prodromal stage of DLB, memory (free recall and visual recognition) and social cognition deficits, as well as weakened visuospatial and praxic abilities. Keywords: Dementia with Lewy bodies, Cognition, Cognitive profile, Prodromal, Mild cognitive impairment
Background Dementia with Lewy bodies (DLB) is the second most common form of degenerative dementia after Alzheimer’s disease (AD), with prevalence rates of up to 5% in the elderly population and up to 30% of all dementia cases [1, 2]. A recent review showed that, on the basis of 2005 revised International Consensus Criteria for DLB [1], DLB * Correspondence: [email protected] 1 Neuropsychology Unit, Neurology Department, University Hospitals of Strasbourg, Strasbourg, France 2 Geriatrics Department, University Hospitals of Strasbourg, Geriatric Day Hospital, Strasbourg, France Full list of author information is available at the end of the article
represents about 4% of dementia cases diagnosed in the community and 7.7% in secondary care [3]. DLB involves a progressive reduction in cognitive functioning, characterised by fluctuations in cognition and alertness, visual hallucinations and parkinsonism. The presence of two or three of these core signs is sufficient for a diagnosis of probable DLB [1]. Patients with DLB are also likely to present with rapid eye movement sleep behaviour disorder (RBD) and severe neuroleptic sensitivity. Other features, which are less specific, are repeated falls, autonomic dysfunction and depression.
© The Author(s). 2017 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
Kemp et al. Alzheimer's Research & Therapy (2017) 9:19
Research on prodromal DLB—that is, the disease is present but cognitive impairment is not sufficient to lead to functional deficits in activities of daily living [4]—is relatively recent. Several features have been described in prodromal DLB [5]. For instance, behavioural and psychiatric symptoms, such as visual hallucinations, RBD, depression, anxiety and delirium, can be present very early and prior to the onset of memory impairment in DLB [6–8]. Similarly, physical symptoms, including constipation, hyposmia and postural dizziness, have been described to appear years before memory loss in prodromal DLB [7]. Pathological studies of Lewy body disease suggest that the olfactory bulb and the peripheral autonomic nervous system, including the enteric nervous system, constitute the first sites of involvement (e.g., [9, 10]). Moreover, we recently demonstrated in a neuroimaging study that patients with prodromal DLB have thinner grey matter in the right insula, superior temporal and orbitofrontal cortices than healthy control subjects (HCs) and patients with prodromal AD [11]. Similarly, we showed that patients with prodromal DLB present with diminished grey matter volumes of bilateral insulae and right anterior cingulate cortex compared with HCs [12]. Functional imaging studies using [18F]fluoro-D-glucose positron emission tomography furthermore showed that patients with prodromal DLB symptoms have occipital hypometabolism [13]. Only a few studies have examined the cognitive profile of prodromal DLB, whereas cognitive impairment has been relatively well documented in patients with moderate DLB, especially compared with patients with AD or patients with Parkinson’s disease (PD) (for reviews, see [14–16]). For instance, moderate DLB is generally associated with prominent deficits on executive function tests (e.g., [17–19]), whereas verbal episodic memory and naming abilities remain rather spared (e.g., [20]). Moreover, numerous studies have shown visuoperceptual and visuospatial impairment (e.g., [14, 21]). Finally, attention is also affected, with reduced sustained and divided attention abilities and increased attentional fluctuations (e.g., [22–24]). Studies on cognition in prodromal DLB also have been focused on the comparison with prodromal AD or PD and have revealed that patients with prodromal DLB have more visuospatial and letter fluency deficits and less memory storage deficits [25–27]. These findings are in line with the suggestion that impairment in nonmemory domains (e.g., executive function, visuospatial abilities) is more likely to progress to DLB than single-domain amnestic mild cognitive impairment (MCI) [25, 27]. Researchers in a recent study assessed cognition in mild and very mild DLB [28]. The authors found that very mild DLB was associated with impairment of attentional/executive, visuospatial, visuoconstructive and naming abilities, as well
Page 2 of 10
as with difficulties in retrieval of episodic memory. With the progression to mild DLB, the authors found that executive function impairment increased, resulting in reduced performance on tests of inhibition, mental flexibility and verbal initiation. The aim of the present study was to draw a cognitive profile of patients with prodromal DLB by means of an extensive neuropsychological evaluation comprising memory, executive function, instrumental function and social cognition tests. Therefore, we compared the performance on cognitive tests of patients with prodromal DLB with normative data as well as with the performance of elderly HCs.
Methods Participants, diagnosis and assessments
Thirty-seven patients with prodromal DLB and 29 HCs were enrolled in the present study. Patients were recruited from the tertiary memory clinic of Strasbourg University Hospitals, Strasbourg, France, including the neurology and geriatrics departments. HCs were recruited from among friends and relatives of the patients or from among participants attending the hospital’s clinical investigation centre. Patients with prodromal DLB were defined as patients with MCI (Petersen’s criteria [29] and McKeith’s criteria [1]) or with probable DLB criteria (i.e., two core symptoms), and this maps onto recent suggestions for potential prodromal DLB criteria [5, 30]. Preservation of independence in functional abilities was assessed in patients and HCs on the basis of four items [31] of the instrumental activities of daily living [32, 33] and the activities of daily living [34] questionnaires. Participants with two or more functional domains impaired, suggesting reduced autonomy, were not included in the present study. Exclusion criteria for all participants included history of alcohol/substance abuse, evidence suggesting alternative neurological or psychiatric explanations for symptoms/cognitive impairment (for patients) or the presence of other severe or unstable medical illness. Patients additionally underwent cerebrospinal fluid (CSF) analysis, including measurement of tau, phosphorylated tau (p-Tau) and amyloid-β (Aβ) 1–42 (INNOTEST β-amyloid(1–42) enzyme-linked immunosorbent assay; Fujirebio, Gent, Belgium). Assessment of medial temporal atrophy by brain magnetic resonance imaging (MRI) was performed in patients and HCs using the standardised Scheltens scale (five categories, 0–4 scale), with 0 corresponding to no atrophy [35]. Patients with concomitant DLB and AD (i.e., meeting both McKeith’s [1] and Dubois’s [36] criteria) were also excluded. More precisely, patients with DLB and two of the following features were excluded: episodic memory (storage) impairment, hippocampal atrophy (Scheltens scale of at minimum 2/4) and CSF abnormalities (at
Kemp et al. Alzheimer's Research & Therapy (2017) 9:19
minimum two abnormal CSF markers among p-Tau, Tau, Aβ42 [37]). Concretely, when hippocampal atrophy or CSF abnormalities were observed in a patient with DLB, performance on the Rappel libre/Rappel indicé à 16 items (RL/ RI-16,) was checked; a patient whose performance indicated storage impairment, testifying to the presence of two of the above-mentioned features, was excluded from analysis. However, a patient presenting solely with hippocampal atrophy, CSF abnormalities or storage impairment was not excluded if the criteria for DLB were met [1]. To assess specific cognitive domains, we used the neuropsychological tests outlined below. Assessment of memory
For the assessment of memory, we used the following tests: The French version of the Free and Cued Selective
Reminding Test (RL/RI-16 [38]): This verbal memory test is based on semantic cuing, which allows controlling for encoding and facilitates retrieval. Sixteen words are presented that are associated with a category cue. Participants are asked to recall the words in three successive trials, then to recognise the 16 items between 32 distractors before recalling them in a 30-minute delayed trial. Each trial includes free recall (FR) and cued recall (CR) tasks whereby the category cue is provided for the items not spontaneously recalled. The total recall (TR) score is the sum of the FR and the CR. The Delayed Matching to Sample-48 items (DMS-48 [39]): The DMS-48 consists of a visual forced-choice recognition test. After an implicit encoding phase where 48 coloured items are presented, an immediate recognition trial (set 1) and a 1-h delayed recognition trial (set 2) are proposed in which participants are asked to choose between the target and a distractor. Two different sets of distractors are used. Forward and backward digit spans [40]: These tests allow evaluation of short-term and working memory. The short-term memory span is the longest list of numbers the participant can recall in correct order immediately after presentation. Backward memory span is the longest list of numbers the participant can recall in reverse order immediately after presentation. Assessment of executive function
For the assessment of executive function, we used the following tests: Frontal Assessment Battery (FAB [41]): The FAB
briefly assesses six cognitive function domains
Page 3 of 10
sustained by the frontal lobes: conceptualisation, mental flexibility, motor programming, sensitivity to interference, inhibitory control and environmental autonomy. Three points are awarded for every perfect response (maximum score 18). Trail Making Test (TMT) A and B [42]: Both parts consist of 25 circles distributed over a sheet of paper. In TMT A, the circles are numbered 1–25, and the participant is asked to draw lines to connect the numbers in ascending order as quickly as possible. In the TMT B, the circles include both numbers (1–13) and letters (A–L). The participant has to draw lines to connect the circles in an ascending pattern as quickly as possible while alternating between the numbers and letters. The completion time and the number of errors are recorded. Formal lexical evocation [43]: The participant is asked to generate as many words as possible that start with the letter P within 2 minutes. Assessment of processing speed
For the assessment of processing speed, we used the digit symbol substitution test [40]. This test involves a key in which the numbers 1–9 are each paired with a unique symbol. Below the key, the numbers 1–9 are shown in random order. The participant is allowed 120 seconds to fill in the corresponding symbol for each number. Assessment of instrumental function
For the assessment of instrumental function, we used the following tests: An oral naming test [44] of 80 pictures (maximum
score 80) and formal semantic evocation [43] were used to evaluate language. Formal semantic evocation consists of generating as many names of animals as possible within 2 minutes. Rey-Osterrieth Complex Figure test (ROCF [45]): Participants were presented with the ROCF stimulus card and asked to draw the same figure. The figure is subcategorised into 18 elements, and these are scored on the basis of their presence, completeness and correct placement (0.5, 1 or 2 points per element; maximum score 36). The following subtests using the Visual Object and Space Perception battery (VOSP [46]) allow the evaluation of visuoperceptual and visuospatial abilities: – Screening: The participant has to identify whether there is a degraded ‘X’ on 20 patterned sheets of paper. One point is given for each correct answer (maximum score 20).
Kemp et al. Alzheimer's Research & Therapy (2017) 9:19
– Incomplete letters: Twenty incomplete letters are shown, and the subject is asked to name or identify them. A point is awarded for each correct answer (maximum score 20). – Dot count: The participant is asked to count how many black dots there are on a white card. There are ten cards. A point is awarded for every correct count (maximum score 10). – Position discrimination: Ten boards are presented. Each board has two squares with a black dot in the centre each. In one of the squares, the point is exactly in the centre, whereas the other point is slightly off-centre. The participant is asked to identify the square in which the black spot is located exactly in the centre. The number of correct answers is recorded (maximum score 10). – ‘Number location’: Ten boards are presented in this test. Each board has two squares arranged one above the other. The top square contains numbers arranged randomly. The bottom square contains only a black dot. The participant is asked to identify which number corresponds to the black dot. Each correct identification earns 1 point (maximum score 10). – Cube analysis: Ten boards are presented. Each board features a design of solid structures. The participant is asked to identify how many solids (cubes) there are on each board. The boards are presented in increasing degree of difficulty (maximum score 10). Praxis is tested by the means of a brief battery [47] evaluating five symbolic gestures (scored 0 or 1 point), five pantomimes (scored 0, 1 or 2 points) and imitation of eight meaningless gestures (scored 0 or 1 point). Evaluation of social cognition
For the evaluation of social cognition, we used the following tests: Mini-Social Cognition & Emotional Assessment
(mini-SEA [48]) test battery: The mini-SEA comprises a facial emotion recognition test and a shortened version of the Faux Pas Recognition Test (FPRT [49]). Emotion recognition is assessed by means of 35 photographs from a series of pictures of facial affect [50]. The faces display one of the six basic emotions (i.e., happiness, sadness, disgust, fear, surprise and anger) or a neutral facial expression. After looking at each photograph, participants choose the emotion that best corresponds to their opinion of that facial expression. The maximum score, indicating best performance, is 35. The FPRT
Page 4 of 10
consists of ten short stories, five with and five without a faux pas. Each story has two types of questions, namely six theory of mind (ToM) questions and two control questions. The ToM questions assess the detection and understanding of faux pas and the understanding of the speaker’s and the listener’s mental states. One point is given for each correct answer on the faux pas questions, and two points are given for each correct rejection of control stories (maximum score 40). Raw scores are converted to weighted scores. Both scores are weighted out of 15, resulting in a total weighted score out of 30. French version of the Reading the Mind in the Eyes (RME) test [51]: This test evaluates the ability of an individual to determine the mental state of another individual by looking at a picture of the latter’s eyes. The task consists of 36 items showing the eye region of 36 different faces in black-and-white photographs. Each picture has four mental state terms printed below it, and the participant has to choose the word that best describes what the person in the photograph is feeling or thinking. The number of correct answers is recorded (maximum score 36). Data analyses
z-Scores were calculated using data derived from normal cohorts ([38–43, 46–48, 52] and Strauss and Spreen, unpublished). They are systematically adjusted for age, as well as for sex and education level when these data are available in the normal cohorts. z-Scores less than or equal to −1.65 are considered pathological. STATISTICA software (version 12.7; Statistica, Tulsa, OK, USA) was used for further statistical evaluation as required. Where appropriate, differences in demographic and clinical data were assessed using parametric (analysis of variance [ANOVA], t tests) and nonparametric (Kruskal-Wallis H, Mann-Whitney U) tests. For categorical measures, χ2 tests were applied. For neuropsychological tests, ANOVA for independent groups was used for the analysis of z-scores, and the nonparametric Kruskal-Wallis H test was used for the analysis of raw scores. For each test statistic, a probability value less than 0.05 was regarded as significant.
Results Participants’ characteristics
Demographic data for patients and HCs are summarised in Table 1. The groups did not differ in terms of age, education, sex and handedness. Cognition
Neuropsychological test results (raw scores and z-scores) of patients and HCs are reported in Table 2.
Kemp et al. Alzheimer's Research & Therapy (2017) 9:19
Page 5 of 10
Table 1 Demographic and clinical characteristics of patients and healthy control subjects Patients with DLB
n
37
29
Age, yearsa
67.19 (8.64)
68.79 (7.94)
NS
Education, years
11.97 (4.14)
13.18 (3.08)
NS
Sex, M/F
18/19
15/14
NS
Handedness, R/L
35/2
27/2
NS
IADL scorea,b
3.75 (0.50)
4 (0)
0.02
ADL scorea,c
5.89 (0.39)
6 (0)
NS
a
HCs
p Value
Characteristic
MCI single/multiple domains Amnestic
0/18
–
–
Non-amnestic
10/9
–
–
Rigidity
28/37 (76)
0/23
